Quinuclidine derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is methoxy and R 2  is selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl and tert-butyl; and the pharmaceutically acceptable salts of such compounds. 
     These compounds are substance P antagonists and useful in the treatment of gastrointestinal disorders, inflammatory disorders, central nervous system disorders and pain.

This application is a continuation-in-part of U.S. Ser. No. 708,404,which was filed on May 31, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel quinuclidine derivatives,pharmaceutical compositions comprising such compounds and the use ofsuch compounds in the treatment and prevention of inflammatory andcentral nervous system disorders, as well as several other disorders.The pharmaceutically active compounds of this invention are substance Preceptor antagonists. This invention also relates to novel intermediatesused in the synthesis of such substance P antagonists.

Substance P is a naturally occurring undecapeptide belonging to thetachykinin family of peptides, the latter being named because of theirprompt stimulatory action on smooth muscle tissue. More specifically,substance P is a pharmacologically active neuropeptide that is producedin mammals (having originally been isolated from gut) and possesses acharacteristic amino acid sequence that is illustrated by D. F. Veber etal. in U.S. Pat. No. 4,680,283. The wide involvement of substance P andother tachykinins in the pathophysiology of numerous diseases has beenamply demonstrated in the art. For instance, substance P has recentlybeen shown to be involved in the transmission of pain or migraine (seeB. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009(1982)), as well as in central nervous system disorders such as anxietyand schizophrenia, in respiratory and inflammatory diseases such asasthma and rheumatoid arthritis, respectively, in rheumatic diseasessuch as fibrositis, and in gastrointestinal disorders and diseases ofthe GI tract such as ulcerative colitis and Crohn's disease, etc. (seeD. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al.,Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).

In the recent past, some attempts have been made to provide antagonistsfor substance P and other tachykinin peptides in order to moreeffectively treat the various disorders and diseases listed above. Thefew such antagonists thus far described are generally peptide-like innature and are therefore too labile from a metabolic point of view toserve as practical therapeutic agents in the treatment of disease. Thenon-peptidic antagonists of the present invention, on the other hand, donot possess this drawback, being far more stable from a metabolic pointof view than the agents referred to above.

The quinuclidine derivatives of this invention are referred togenerically in PCT Patent Application PCT/US 89/05338, filed Nov. 20,1989 and United States patent application Ser. No. 557,442, filed Jul.23, 1990, both of which are assigned in common with the presentapplication. Other quinuclidine derivatives that exhibit activity assubstance P receptor antagonists are referred to in PCT patentapplication PCT/US 91/02853, entitled "3-Amino-2-Aryl Quinuclidines" andfiled on Apr. 25, 1991 and in PCT patent application PCT/US 92/03369,entitled "Quinuclidine Derivatives" and filed on May 14, 1991. Theseapplications are also assigned in common with the present application.

Piperidine derivatives and related heterocyclic nitrogen containingcompounds that are useful as substance P antagonists are referred to inUnited States patent application Ser. No. 619,361, filed Nov. 28, 1990and United States patent application Ser. No. 590,423, filed Sep. 28,1990, both of which are assigned in common with the present application.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein R¹ is methoxy and R² is independently selected from the groupconsisting of isopropyl, tert-butyl, methyl, ethyl and sec-butyl; andthe pharmaceutically acceptable salts of such compounds.

Specific compounds of this invention include the following:

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;

and the pharmaceutically acceptable salts of such compounds.

The present invention also relates to a pharmaceutical composition fortreating or preventing a condition selected from the group consisting ofinflammatory diseases (e.g., arthritis, psoriasis, asthma andinflammatory bowel disease), anxiety, depression or dysthymic disorders,colitis, psychosis, pain, allergies such as eczema and rhinitis, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, hypertension, vasospastic diseases such as angina, migraine andReynaud's disease, fibrosing and collagen diseases such as sclerodermaand eosinophilic fascioliasis, reflex sympathetic dystrophy such asshoulder/hand syndrome, addiction disorders such as alcoholism, stressrelated somatic disorders, peripheral neuropathy, neuralgia,neuropathological disorders such as Alzheimer's disease, AIDS relateddementia, diabetic neuropathy and multiple sclerosis, disorders relatedto immune enhancement or suppression such as systemic lupuserythematosus, and rheumatic diseases such as fibrositis in a mammal,including a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga condition selected from the group consisting of inflammatory diseases(e.g., arthritis, psoriasis, asthma and inflammatory bowel disease),anxiety, depression or dysthymic disorders, colitis, psychosis, pain,allergies such as eczema and rhinitis, chronic obstructive airwaysdisease, hypersensitivity disorders such as poison ivy, hypertension,vasospastic diseases such as angina, migraine and Reynaud's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, peripheral neuropathy, neuralgia, neuropathological disorderssuch as Alzheimer's disease, AIDS related dementia, diabetic neuropathyand multiple sclerosis, disorders related to immune enhancement orsuppression such as systemic lupus erythematosus, and rheumatic diseasessuch as fibrositis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such condition.

The present invention also relates to a pharmaceutical composition forantagonizing the effects of substance P in a mammal, including a human,comprising a substance P antagonizing amount of a compound of formula I,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a method of antagonizing theeffects of substance P in a mammal, including a human, comprisingadministering to said mammal a substance P antagonizing amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder in a mammal, including a human,resulting from an excess of substance P, comprising a substance Pantagonizing amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga disorder in a mammal, including a human, resulting from an excess ofsubstance P, comprising administering to said mammal a substance Pantagonizing amount of a compound of the formula I, or apharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition fortreating or preventing a condition selected from the group consisting ofinflammatory diseases (e.g., arthritis, psoriasis, asthma andinflammatory bowel disease), anxiety, depression or dysthymic disorders,colitis, psychosis, pain, allergies such as eczema and rhinitis, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, hypertension, vasospastic diseases such as angina, migraine andReynaud's disease, fibrosing and collagen diseases such as sclerodermaand eosinophilic fascioliasis, reflex sympathetic dystrophy such asshoulder/hand syndrome, addiction disorders such as alcoholism, stressrelated somatic disorders, peripheral neuropathy, neuralgia,neuropathological disorders such as Alzheimer's disease, AIDS relateddementia, diabetic neuropathy and multiple sclerosis, disorders relatedto immune enhancement or suppression such as systemic lupuserythematosus, and rheumatic diseases such as fibrositis in a mammal,including a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in antagonizingthe effect of substance P at its receptor site, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a method of treating or preventinga condition selected from the group consisting of inflammatory diseases(e.g., arthritis, psoriasis, asthma and inflammatory bowel disease),anxiety, depression or dysthymic disorders, colitis, psychosis, pain,allergies such as eczema and rhinitis, chronic obstructive airwaysdisease, hypersensitivity disorders such as poison ivy, hypertension,vasospastic diseases such as angina, migraine and Reynaud's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, peripheral neuropathy, neuralgia, neuropathological disorderssuch as Alzheimer's disease, AIDS related dementia, diabetic neuropathyand multiple sclerosis, disorders related to immune enhancement orsuppression such as systemic lupus erythematosus, and rheumatic diseasessuch as fibrositis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, effective in antagonizingthe effect of substance P at its receptor site.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder in a mammal, including a human, thetreatment or prevention of which is effected or facilitated by adecrease in substance P mediated neurotransmission, comprising an amountof a compound of the formula I, or a pharmaceutically acceptable saltthereof, effective in antagonizing the effect of substance P at itsreceptor site, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga disorder in mammal, including a human, the treatment or prevention ofwhich is effected or facilitated by a decrease in substance P mediatedneurotransmission, comprising administering to said mammal an amount ofa compound of the formula I, or a pharmaceutically acceptable saltthereof, effective in antagonizing the effect of substance P at itsreceptor site.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder in a mammal, including a human, thetreatment or prevention of which is effected or facilitated by adecrease in substance P mediated neurotransmission, comprising an amountof a compound of the formula I, or a pharmaceutically acceptable saltthereof, effective in treating or preventing such disorder, and apharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventinga disorder in mammal, including a human, the treatment or prevention ofwhich is effected or facilitated by a decrease in substance P mediatedneurotransmission, comprising administering to said mammal an amount ofa compound of the formula I, or a pharmaceutically acceptable saltthereof, effective in treating or preventing such disorder.

The compounds of this invention, have chiral centers and therefore existin different enantiomeric forms. This invention relates to all opticalisomers and all stereoisomers of compounds of the formula I, andmixtures thereof.

The compounds of this invention include compounds identical to thosedescribed above but for the fact that one or more hydrogen, nitrogen orcarbon atoms are replaced by isotopes thereof (e.g., tritium orcarbon-14 isotopes). Such compounds are useful as research anddiagnostic tools in metabolism pharmokinetic studies and in bindingassays. Specific applications in research include radioligand bindingassays, autoradiography studies and in vivo binding studies, whilespecific applications in the diagnostic area include studies of thesubstance P receptor in the human brain in in vivo binding in therelevant tissues for inflammation, e.g. immune-type cells or cells thatare directly involved in inflammatory bowel disorders and the like.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention may be prepared by subjecting a compoundof the formula ##STR3## having the same absolute stereochemistry as thedesired compound of formula I, to hydrolytic removal of themethoxybenzyl group to produce the corresponding compound of the formula##STR4## having the same stereochemistry, and then reacting the compoundof formula III so formed with an aldehyde of the formula ##STR5## in thepresence of a reducing agent.

Hydrolytic removal of the methoxybenzyl group is generally carried outusing a strong mineral acid such as hydrochloric, hydrobromic orhydroiodic acid, at a temperature from about room temperature to aboutthe reflux temperature of the acid. Preferably, the reaction isconducted in hydrobromic acid at the reflux temperature. This reactionis usually carried out for a period of about 2 hours.

Alternatively, the hydrolytic removal of the methoxybenzyl group in theabove procedure may be replaced by hydrogenolytic removal of such group.Hydrogenolytic removal is generally accomplished using hydrogen in thepresence of a metal containing catalyst such as platinum or palladium.This reaction is usually conducted in a reaction inert solvent such asacetic acid or a lower alcohol, at a temperature from about 0° C. toabout 50° C. The methoxybenzyl group may also be removed, alternatively,by treating the compound of formula II with a dissolving metal such aslithium or sodium in ammonia at a temperature from about -30° C. toabout 78° C., or with a formate salt in the presence of palladium orwith cyclohexane in the presence of palladium.

Preferably, the methoxybenzyl group is removed by treating the compoundof formula II with hydrogen in the presence of palladium hydroxide oncarbon in methanol containing hydrochloric acid at a temperature ofabout 25° C.

The resulting compound of formula III may be converted into the desiredcompound of formula I by reaction with the appropriate aldehyde offormula IV in the presence of a reducing agent. The reaction istypically carried out using a reducing agent such as sodiumcyanoborohydride, sodium triacetoxyborohydride, sodium borohydride,hydrogen and a metal catalyst, zinc and hydrochloric acid, boranedimethylsulfide or formic acid at a temperature from about -60° C. toabout 50° C. Suitable reaction inert solvents for this reaction includelower alcohols (e.g., methanol, ethanol and isopropanol), acetic acid,methylene chloride and tetrahydrofuran (THF). Preferably, the solvent ismethylene chloride, the temperature is about 25° C., and the reducingagent is sodium triacetoxyborohydride.

Alternatively, the reaction of a compound of the formula III with acompound of the formula IV may be carried out in the presence of adrying agent or using an apparatus designed to remove azeotropically thewater generated, to produce an imine of the formula ##STR6## which isthen reacted with a reducing agent as described above, preferably withsodium triacetoxyborohydride at about room temperature. The preparationof the imine is generally carried out in a reaction inert solvent suchas benzene, xylene or toluene, preferably toluene, at a temperature fromabout 25° C. to about 110° C., preferably at about the refluxtemperature of the solvent. Suitable drying agents/solvent systemsinclude titanium tetrachloride/dichloromethane, titaniumisopropoxide/dichloromethane and molecular sieves/THF. Titaniumtetrachloride/dichloromethane is preferred.

Compounds of the formula III may also be converted into compounds of theformula I having the same stereochemistry by reaction with theappropriate compound of the formula ##STR7## wherein L is a leavinggroup (e.g., chloro, bromo, iodo or mesylate). This reaction isgenerally carried out in a reaction inert solvent such asdichloromethane or THF, preferably dichloromethane, at a temperaturefrom about 0° C. to about 60° C., preferably at about 25° C.

Compounds of the formula III may also be converted into compounds of theformula I having the same stereochemistry by reacting them with theappropriate compound of the formula ##STR8## wherein L is defined asabove or is imidazole, and then reducing the resulting amide. Thisreaction is typically carried out in an inert solvent such as THF ordichloromethane at a temperature from about -20° C. to about 60° C.,preferably in dichloromethane at about 0° C. Reduction of the resultingamide is accomplished by treatment with a reducing agent such as boranedimethylsulfide complex, lithium aluminum hydride or diisobutylaluminumhydride in an inert solvent such as ethyl ether or THF. The reactiontemperature may range from about 0° C. to about the reflux temperatureof the solvent. Preferably, the reduction is accomplished using boranedimethylsulfide complex in THF at about 60° C.

The novel compounds of the formula I and the pharmaceutically acceptablesalts thereof are useful as substance P antagonists, i.e., they possessthe ability to antagonize the effects of substance P at its receptorsite in mammals, and therefore they are able to function as therapeuticagents in the treatment of the aforementioned disorders and diseases inan afflicted mammal.

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the Formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained.

Those compounds of the formula I which are also acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of formulae I, IIand III. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product of yields of the desired final product.

The compounds of Formula I and their pharmaceutically acceptable saltsexhibit substance P receptor binding activity and therefore are of valuein the treatment and prevention of a wide variety of clinical conditionsthe treatment or prevention of which are effected or facilitated by adecrease in substance P mediated neurotransmission. Such conditionsinclude inflammatory diseases (e.g., arthritis, psoriasis, asthma andinflammatory bowel disease), anxiety, depression or dysthymic disorders,colitis, psychosis, pain, allergies such as eczema and rhinitis, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, hypertension, vasospastic diseases such as angina, migraine andReynaud's disease, fibrosing and collagen diseases such as sclerodermaand eosinophilic fascioliasis, reflex sympathetic dystrophy such asshoulder/hand syndrome, addiction disorders such as alcoholism, stressrelated somatic disorders, peripheral neuropathy, neuralgia,neuropathological disorders such as Alzheimer's disease, AIDS relateddementia, diabetic neuropathy and multiple sclerosis, disorders relatedto immune enhancement or suppression such as systemic lupuserythematosus, and rheumatic diseases such as fibrositis. Hence, thesecompounds are readily adapted to therapeutic use as substance Pantagonists for the control and/or treatment of any of the aforesaidclinical conditions in mammals, including humans.

The compounds of the formula I and the pharmaceutically acceptable saltsthereof can be administered via either the oral, parenteral or topicalroutes. In general, these compounds are most desirably administered indosages ranging from about 0.5 mg to about 500 mg per day, althoughvariations will necessarily occur depending upon the weight andcondition of the subject being treated and the particular route ofadministration chosen. Variations may occur depending upon the speciesof animal being treated and its individual response to said medicament,as well as on the type of pharmaceutical formulation chosen and the timeperiod and interval at which such administration is carried out. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effect, provided that suchlarger doses are first divided into several small doses foradministration throughout the day.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the three routes previously indicated, and such administrationmay be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of this invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a therapeutic compound ofthe present invention in either sesame or peanut oil or in aqueouspropylene glycol may be employed. The aqueous solutions should besuitably buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic. These aqueous solutions aresuitable for intravenous injection purposes. The oily solutions aresuitable for intraarticular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell known to those skilled in the art.

Additionally, it is also possible to administer the compounds of thepresent invention topically when treating inflammatory conditions of theskin and this may preferably be done by way of creams, jellies, gels,pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The activity of the compounds of the present invention as substance Pantagonists is determined by their ability to inhibit the binding ofsubstance P at its receptor sites in bovine caudate tissue, employingradioactive ligands to visualize the tachykinin receptors by means ofautoradiography. The substance P antagonizing activity of the hereindescribed compounds may be evaluated by using the standard assayprocedure described by M. A. Cascieri et al., as reported in the Journalof Biological Chemistry, Vol. 258, p. 5158 (1983). This methodessentially involves determining the concentration of the individualcompound required to reduce by 50% the amount of radiolabelled substanceP ligands at their receptor sites in said isolated cow tissues, therebyaffording characteristic IC₅₀ values for each compound tested.

In this procedure, bovine caudate tissue is removed from a -70° C.freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris(i.e., trimethamine which is 2-amino-2-hydroxymethyl-1, 3-propanediol)hydrochloride buffer having a pH of 7.7. The homogenate is centrifugedat 30,000× G for a period of 20 minutes. The pellet is resuspended in 50volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000×G for another twenty- minute period. The pellet is then resuspended in40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM ofcalcium chloride, 2 mM of magnesium chloride, 40 g/ml of bacitracin, 4μg/ml of leupeptin, 2 μg of chymostatin and 200 g/ml of bovine serumalbumin. This step completes the production of the tissue preparation.

The radioligand binding procedure is then carried out in the followingmanner, viz., by initiating the reaction via the addition of 100 μl ofthe test compound made up to a concentration of 1 μM, followed by theaddition of 100 μl of radioactive ligand made up to a finalconcentration 0.5 mM and then finally by the addition of 800 μl of thetissue preparation produced as described above. The final volume is thus1.0 ml, and the reaction mixture is next vortexed and incubated at roomtemperature (ca. 20° C.) for a period of 20 minutes. The tubes are thenfiltered using a cell harvester, and the glass fiber filters (WhatmanGF/B) are washed four times with. 50 mM of Tris buffer (pH 7.7), withthe filters having previously been presoaked for a period of two hoursprior to the filtering procedure. Radioactivity is then determined in aBeta counter at 53% counting efficiency, and the IC₅₀ values arecalculated by using standard statistical, methods.

The anti-psychotic activity of the compounds of the present invention asneuroleptic agents for the control of various psychotic disorders isdetermined primarily by a study of their ability to suppress substanceP-induced or substance P agonist induced hypermotility in guinea pigs.This study is carried out by first dosing the guinea pigs with a controlcompound or with an appropriate test compound of the present invention,then injecting the guinea pigs with substance P or a substance P agonistby intracerebral administration via canula and thereafter measuringtheir individual locomotor response to said stimulus.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples.

EXAMPLE 1

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

A. (2S,3S)-2-(2-diphenylmethyl-1-azabicyclo 2.2.2!-octan-3-amine

(2S,3S)-N-(2-methoxyphenyl)methyl-1-azabicyclo 2.2.2!-octan-3-amine(4.12 g, 10 mmol) was hydrogenated at room temperature in methanol(MeOH) (40 ml)/6N hydrochloric acid (HCl) (10 ml) by using 20% palladiumhydroxide on carbon (0.2 g) at 2.5 kg/cm² of hydrogen for 60 hours. Thereaction was filtered and the filtrate was concentrated to give thecrude product, which was crystallized from ethanol.

B.(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

To a solution of a 5-isopropyl-2-methoxybenzaldehyde (748 mg, 4.2 mmol)and (2S,3S)-2-diphenylmethyl-1-azabicyclo 2.2.2!octan-3-amine (4 mmol)in methylene chloride (CH₂ Cl₂) (40 ml) was added in portionstriacetoxyborohydride (933 mg, 4.4 mmol). The mixture was stirred untilthe amine disappeared. The solution was carefully neutralized with anice-cooled saturated sodium bicarbonate (NaHCO₃) solution. The organiclayer was washed with water, dried over magnesium sulfate (MgSO₄), andconcentrated to give the product (1.82 g). To a solution of the productin acetone was added equivalent methansulfonate acid. Then theprecipitated mesylate salt was collected and dried under vacuum.

The title compounds of Examples 2-15 were prepared by a proceduresimilar to that of Example 1.

EXAMPLE 2

(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

M.p.: 240° C.

IR (KBr) cm⁻¹ : 3410, 2980, 1640, 1500, 1455, 1200, 1060, 710.

¹ H NMR (CDCl₃) δ: 7.5-7.2 (10H, m), 7.10 (1H, m) 8.40 (1H, br), 6.63(1H, d, J=8 Hz), 6.39 (1H, br s), 4.55 (1H, m) 4.12 (1H, m), 3.80-3.30(5H, m), 3.53 (3H, s), 3.25 (1H, m), 3.20 (1H, m), 2.47 (3H, s), 2.42(1H, m), 2.21 (3H, s), 2.30-2.16 (4H, m).

EXAMPLE 3

(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

M.p.: 151° C.

IR (KBr) cm⁻¹ : 3420, 2970, 1640, 1510, 1460, 1195, 1060, 785.

¹ H NMR (CDCl₃) δ: 10.9 (1H, br), 8.18 (1H, br) 7.85-7.15 (11H, m), 6.86(1H, m), 6.68 (1H, d, J=8.8 Hz), 5.57 (1H, br) 5.45 (1H, m) 5.05 (1H, d,J=13.2 Hz), 4.24-3.65 (5H, m), 3.48 (3H, s), 3.50-3.35 (3H, m), 2.92(1H, m), 2.61 (6H, s), 2.8-2.2 (6H, m), 2.54 (2H, m), 2.30-1.80 (2H, m),1.21 (3H, m).

EXAMPLE 4

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

M.p.: 221° C.

IR (KBr) cm⁻¹ : 3430, 2960, 1600, 1500, 1455, 1245, 1160, 1040, 710.

¹ H NMR (CDCl₃) δ: 8.40 (1H, br) 7.5-7.2 (10H, m) 7.06 (1H, m), 6.67(1H, d, J=8.4 Hz), 6.56 (1H, br, s) 4.58 (1H, m) 4.24 (1H, m), 3.6-3.3(5H, m), 3.53 (3H, s), 3.24 (1H, m), 3.22 (1H, m), 2.78 (1H, sep, J=7Hz), 2.48 (4H, s), 2.42 (1H, m), 2.27 (1H, m), 1.99 (2H, m), 1.76 (1H,m), 1.20 (6H, dd, J=2.9 Hz, 7 Hz).

EXAMPLE 5

(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methanesulfonic acid salt

M.p.: 224° C.

IR (KBr) cm⁻¹ : 3440, 2960, 1610, 1500, 1455, 1220, 1160, 1035, 755,710, 560.

¹ H NMR (CDCl₃) δ: 8.41 (1H, br), 7.5-7.2 (10H, m) 7.00 (1H, m), 6.67(1H, d, J=8.4 Hz), 6.52 (1H, br, s) 4.58 (1H, d, J=11.7 Hz), 4.25 (1H,m), 3.70-3.35 (5H, m), 3.53 (3H, s), 3.21 (2H, m), 2.46 (3H, s), 2.43(1H, m), 2.26 (1H, m), 2.04 (1H, m), 2.00-1.60 (3H, m), 1.52 (2H, m),1.18 (2H, m), 0.82 (3H, m).

We claim:
 1. A compound of the formula ##STR9## wherein R¹ is methoxyand R² is selected from isopropyl, ethyl and sec-butyl; or apharmaceutically acceptable salt of such compound.
 2. A compoundaccording to claim 1, wherein said compound is selected from the groupconsistingof:(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine;(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine; and the pharmaceutically acceptable salts of suchcompounds. 3.(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine methansulfonate. 4.(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo2.2.2!octan-3-amine dihydrochloride.
 5. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition according to claim 5, wherein the concentration of thecompound according to claim 1 is from about 5.0% to about 70.0% byweight.